CH658655A5 - NEW ISOXAZOLES AND METHOD FOR THEIR PRODUCTION. - Google Patents

Description

The invention relates to new isoxazoles of the general formula (I)

y-CH2

(i)

and or

,H

HO

H 1> 1

* 0

(IIa)

reacted with a strong base and the product obtained isolated.

13. A process for the preparation of isoxazole derivatives of the general formula I according to claim 1, in which X and Y are groups of the formula —COOZ, characterized in that the compound of the formula II and / or IIa

(II)

A0J'XqJ

and or

50

and a process for their manufacture. Stand in the general formula (I)

X and Y independently of one another for nitrile group, optionally activated carboxyl group or groups of the formulas - COOZ or —CONRR ', in which Z represents an alkyl group with 1-6 carbon atoms, R and R' represent hydrogen, phenyl or benzyl group or form a heterocycle together with the nitrogen atom or,

X and Y together form an anhydride group of the formula o = c-o-c = o.

I I

The compounds of the general formula (I) can be used primarily as intermediates in the antibiotic thienamycin, which has a broad spectrum of activity. For this purpose, they are converted by catalytic hydrogenation into the corresponding compounds of the general formula (IX), in which the meaning of X and Y is the same as above.

3rd

658 655

y

—GH

2 ^^ XC-CH3

II

/ n \ h- °

(IX)

H

tert-butoxide or alkali metal alcoholate with a dialkyl malonate to the compound of the general formula (IV) and / or (IVa) reacted (Z = alkyl group with 1-6 carbon atoms).

(IV)

The compounds of the general formula (IX) are reduced, then condensed with benzaldehyde and reduced again, whereby the lactones of the general formula (X) are formed.

HOOG

(X)

ZOOG ZOOC

C.

II 0

H

(IVa)

nh-ch2

HCl which can be converted to thienamycin according to European patent application No. 32,400.

It has been found that the compounds of the general formula (I) or (IX) can be prepared from easily accessible starting materials with simple process steps using a peculiar method of double ring transformation; the compounds of the general formula (X) can then be obtained from them.

According to the process, the acetoacetic ester of the formula (VIII)

C2H5OOC - Ç = CH - QC2H5

C = 0 (viii)

/ Nd-

'N

These tautomers are then converted to compounds of the general formula (III) and / or (purple) with hydroxylamine hydrochloride

(III)

jr zocc-

-H

cf ^ 0 / N H3C ^ X)

II

N

(purple)

ch3

implemented and formed from these with acetic acid in the presence of sulfuric acid or another strong acid, the compounds of all-with hydroxylamine hydrochloride in the presence of an acid acceptor 40 formula (II) and / or (IIa).

to the isoxazole derivative of the formula (VII)

C2H5OOC-

h3CN)

N

(VII)

0 ^ 0 / N

(Ii)

'H

implemented and the isoxazolecarboxylic acid of the formula (VI) formed from this by hydrolysis:

H00C-

HO ^ O ^

(Ha)

, N

H3C ^ 0

M

(VI)

This compound is activated on the carboxyl group. Examples of possible activators are phosphorus halides, thionylchloride or chloroformate. The compound of the general formula (V) obtained in this way

0

Q — C-

, ~ 1, H3cNr ^

(V)

in which Q represents halogen atom or alkoxycarbonyl group having 1-5 carbon atoms, in the presence of magnesium, potassium in the general formulas (III), (Illa), (II) and (IIa), Z represents an alkyl group having 1-6 carbon atoms. The compounds 55 of the general formulas (II) and (IIa) are the starting materials of the process according to the present invention; from them a strong base is used to prepare the compound of the general formula (I) which contains a carboxyl group as the substituent Y and a nitrile group as the substituent X, and by further reaction 60 the other compounds of the general formula (I) are obtainable.

The compounds of the general formulas (V), (IV), (IVa), (III), (Illa), (II), (IIa) and (I) are new compounds. Under the reaction conditions used, the possible 65 tautomer pairs corresponding to formulas (IV), (III) and (II) are in tautomeric form.

The invention accordingly also relates to a process for the preparation of the isoxazole derivatives of the general formula (I)

658 655

4th

wherein

X and Y independently of one another represent nitrile group, optionally activated carboxyl group or groups of the formulas - COOZ or —CONRR ', in which Z represents an alkyl group with 1-6 carbon atoms and R and R' represent hydrogen, phenyl or benzyl group or form a heterocycle with the nitrogen atom or

X and Y together form an anhydride group of the formula o = c-o-c = o. ''

It is characteristic of the process that compounds of the formulas (II) and / or (IIa) are reacted with a strong base and the product a) obtained which contains a carboxyl group as substituent Y and a nitrile group as substituent X is isolated, or b) if desired hydrolyzed and the compound of general formula (I) obtained as substituents X and Y is isolated, or c) if desired, the product prepared according to process a) is activated on the carboxyl group, optionally the compound obtained which contains an activated carboxyl group as substituent Y. general formula (I) isolated or with an amine suitable for the delivery of a group - NRR '- in which the meaning of R and R' is the same as above - and the obtained, as substituent X a nitrile group and as substituent Y a —CONRR 'Group-containing compound of general formula (I) isolated, or d) if desired, according to the process na) or b) reacting the product obtained in the presence of a catalyst with an alkanol having 1-6 carbon atoms and isolating the compound of the general formula (I) containing substituents X and Y of the formula —COOZ, or e) if desired, after the the process b) product is reacted with a dehydrating agent and the compound of the general formula (I) in which X and Y together represent an acid anhydride group is isolated, or f) if desired, the product obtained by process d) with a product for release a group —NRR '- in which the meaning of R and R' is the same as above - converts suitable amine and the resulting compound, as substituent Y, is a group —CONRR ”and as substituent X is a group —COOZ, of the general formula (I ) isolated.

According to process a), the compounds of the formula (II) and / or (IIa) are reacted with a strong base and a compound of the general formula (I) with Y = carboxyl group and X = nitrile group is obtained. Alkali metal hydroxides, alkali metal alcoholates, diazabicyclo [5.4.0] undec-5-ene (DBU) etc. are used as strong bases.

According to process b), the product of process a) is hydrolyzed. The hydrolysis is preferably carried out in the presence of an acid, but basic hydrolysis is also possible. In the product obtained, Y and X represent COOH.

In the sense of process c), the product of process a) is first treated with a carboxyl group activator. As such primarily phosphorus halides, thionyl chloride, acid anhydrides or mixed anhydrides come into question. The compound activated on the carboxyl group is then reacted with compounds which give off esterifying groups Z or groups —NRR ”. Alkanols with 1-6 carbon atoms, aniline, benzylamine or morpholine are preferably used as the reagent. If an alkanol with 1-6 carbon atoms is used as the reagent, the reaction is carried out in the presence of an acid acceptor, preferably a tertiary amine. If the reagent is an amine, its excess serves as an acid acceptor. If an alkyl (chloroformate) having 1-5 carbon atoms was used as the activating agent, then in the presence of an acid acceptor, the compound containing a —COOZ group as the substituent Y is obtained directly. Process c) provides compounds of the general formula (I) which contain a nitrile group as substituent X and a group - COOZ or - CONRR 'as substituent Y.

io According to process d), the product of process a) or b) is esterified. Alkanols with 1-6 carbon atoms are preferably used as ester formers in the presence of an acid catalyst. In the product obtained, Y and X stand for - COOZ.

According to process e), the product of process b) 15 is treated with a dehydrating agent. Alkane carboxylic anhydrides are preferably used as such, and the reaction is carried out at elevated temperature, preferably at the boiling point of the reaction mixture. The connection creates a connection in which Y and X together form a group

20 o = c-o-c = o form. ''

In the sense of process f), the product of process d) is reacted with an amine which gives off group NRR '. The reaction is carried out at an elevated temperature. In the product obtained, Y is —CONRR 'and X is —COOZ.

The products obtained by any of the methods according to the invention can be converted to compounds of the formula (IX) by reduction.

30 The process is explained in more detail using Examples 1-16. Examples 17-22 illustrate the preparation of the compounds of formula (IX). Example 23 shows the preparation of the compound of formula (X). The invention is not restricted to the exemplary embodiments.

35 Example 1

Ethyl (5-methyl-4-isoxazole carboxylate)

350 g (1.88 mol) of a-ethoxymethylene acetecetester are dissolved in 400 ml of ethanol. The solution is mixed with the solution of 154 g of 40 (2.2 mol) of hydroxylamine hydrochloride in 500 ml of water and with 180 g (2.2 mol) of sodium acetate and then boiled for 30 minutes. The reaction mixture is poured into 2 liters of water, the phases are separated from one another, the aqueous phase is shaken three times with 250 ml of dichloromethane and the dichloromethane-4S solution is added to the organic phase. The organic phase is washed with 2 × 300 ml of water, the phases are separated from one another, and the dichloromethane is distilled off in vacuo. The residue can be used for further reaction steps without purification.

50 Yield: 281 g (96%) of the title compound Boiling point: 58-60; C / 0.3 mmHg

'H NMR (CDC13): 5 1.41 (3H), 2.7 s (3H), 4.25 q (2H), 8.5 s (IH).

55 Example 2

5-methyl-4-isoxazole carboxylic acid

281 g (1.81 mol) of the compound prepared according to Example 1 are boiled in a mixture of 200 ml of glacial acetic acid, 200 ml of water and 60 200 ml of concentrated aqueous hydrochloric acid for 8 hours. Then the reaction mixture is evaporated to dryness. The residue is mixed with 400 ml of acetone and evaporated again. The residue is air dried.

Yield: 201 g (87%) of the title compound 65 Melting point: 146-147 'C (toluene)

Due to the melting point and the IR spectrum, the connection is identical to that of Kochetkov et al. described connection (CA 1959 9187Ì).

5

658 655

Example 3

5-methyl-4-isoxazole carboxylic acid chloride

350 ml of thio-nyl chloride are added to 201 g (1.58 mol) of the compound prepared according to Example 2 with stirring over the course of 10 minutes, and the reaction mixture is then refluxed for one hour on an oil bath (120 ° C.). After the excess thionyl chloride has been distilled off in vacuo, the residue is purified by vacuum distillation.

Yield: 191 g (83%) of the title compound Boiling point: 100-102 ° C / 18 mmHg

Elemental analysis for CSH4C1N02 (M = 145.55):

Calculated: C 41.16 H 2.77 N 9.68 Cl 24.36% Found: C 41.19 H 2.92 N 9.57 Cl 24.22%

Example 4

Thyl-f l-ethoxycarbonyl-2-hydroxy-2- (5-methyl-isoxazol-4-yl)] acrylate

66.5 g (2.73 gram atom) of magnesium shavings are boiled in a mixture of 175 ml of benzene, 20 ml of ethanol and 1 ml of carbon tetrachloride. The mixture of 436 ml (2.73 mol) of diethyl malonate, 600 ml of benzene and 140 ml of ethanol is added to the boiling mixture within one hour, and the reaction mixture is boiled for a further 3 hours. Then about 500 ml of solvent are distilled off from the mixture. The solution of 191 g (1.31 mol) of the compound prepared according to Example 3 in 200 ml of benzene is added to the residue with vigorous stirring at 35-40 ° C. The reaction mixture is stirred for a further 10 minutes and then cooled. The mixture containing precipitation is mixed with 230 ml of glacial acetic acid and 1800 ml of water. The organic phase is separated off. Concentrated aqueous hydrochloric acid is added to the aqueous phase and extracted with 2 × 300 ml of benzene. The combined benzene phases are washed with the mixture of 40 ml of concentrated hydrochloric acid and 350 ml of water, then twice with 400 ml of water each time, filtered, and the benzene is distilled off from the organic phase in vacuo. The residue is mixed with 600 ml of dichloromethane, this is distilled off, then 600 ml of n-heptane are added, this is also distilled off, and finally the excess of diethyl malonate is also distilled off on an oil bath (135-140 ° C.) (boiling point: 70- 80 ° C / 0.4 mmHg, about 230 ml). The residue is cooled and crystallized by standing.

Yield: 292 g (83%) of the title compound Boiling point: 140-144 ° C / 0.4 mmHg Melting point: 56 ° C (ether / n-hexane = 1: 1)

■ H NMR (CDC13): 8 1.3 t (3H), 2.7 s (3H), 4.25 q (2H), 4.9 s (IH), 8.5 s (IH).

Example 5

Ethyl- [3- (5-methyl-isoxazol-4-yl) -5-hydroxy-4-isoxazole-carboxylate]

292 g (1.08 mol) of the compound prepared according to Example 4 are boiled in one liter of ethanol together with 100 g (1.45 mol) of hydroxylamine hydrochloride for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved warm in 1.2 liters of dichloromethane and the solution is filtered. The filtered precipitate is washed with 2 x 200 ml of warm dichloromethane and the washing liquid is combined with the filtrate. The solution is washed with 2 × 300 ml of water and the organic phase is evaporated in vacuo. 750 ml of dichloromethane are added to the evaporation residue, this is distilled off, the residue is triturated with 120 ml of ethyl acetate and left to stand at 0.degree. The crystals are filtered off, washed with 2 x 25 ml of cold ethyl acetate and then with 2 x 200 ml of n-hexane and air-dried.

Yield: 154 g (62%) of the title compound Melting point: 153-154 ° C (ethyl acetate)

■ H NMR (DMSO-d6): 8 1.1t (3H), 2.4 s (3), 4.0 q (2H), 8.6 s (IH), 11.0 s (IH).

Example 6

5 3- (5-methyl-isoxazol-4-yl) -4,5-dihydroisoxazol-5-one

154 g (0.646 mol) of the compound prepared according to Example 5 are boiled in 650 ml of acetic acid in the presence of 14 ml of concentrated sulfuric acid for 15 minutes. After intensive CO 2 evolution has ceased, 40 g of 10 sodium acetate are added to the solution and the mixture is evaporated in vacuo. 300 ml of water are added to the evaporation residue and shaken once with 500 ml, then twice with 300 ml of dichloromethane each. The organic phases are combined, washed twice with 250 ml of water each time, and the organic phase is evaporated. 500 ml of dichloromethane and then 300 ml of n-heptane are first distilled off from the residue. The residue is recrystallized from 130 ml of 2-propanol. The crystals are filtered off, washed twice with 15 ml of ice-cold 2-propanol each, then twice with 75 ml of n-hexanol and air-dried.

20 Yield: 93.4 g (87%) of the title compound Melting point: 94-95 ° C

'H NMR (CDCI3): 5 2.7 s (3H), 3.8 s (2H), 8.4 s (IH).

Example 7

25 (5-methyl-4-cyano-3-isoxazole) acetic acid

93.4 g (0.563 mol) of the compound prepared according to Example 6 are added all at once to the solution of 57 g (1.42 mol) sodium hydroxide prepared with 350 ml water at 25 ° C. The mixture is stirred for 2 minutes, the temperature rising to about 3 ° 7qo q. The reaction mixture is cooled with ice water and 145 ml of concentrated hydrochloric acid are added. After cooling again, the mixture is extracted first with 350 ml, then twice with 150 ml dichloromethane. The organic phase is washed with 2 x 80 ml of saturated aqueous sodium chloride solution 35 and the organic phase is evaporated in vacuo. 250 ml of dichloromethane and then 150 ml of n-hexane are distilled off from the residue. The residue crystallizes on standing. Yield: 91.5 g (98%) of the title compound Melting point: 90-91 ° C. (benzene)

40 1 H NMR (CDCI3): 8 2.6 s (3H), 4.0 s (2H).

Example 8

(5-methyl-4-carboxy-3-isoxazole) acetic acid

45 91.5 g (0.55 mol) of the compound prepared according to Example 7 are boiled in a mixture of 100 ml of water and 100 ml of concentrated hydrochloric acid for 3 hours. The reaction mixture is cooled, the precipitated product is filtered off, washed with 2 × 40 ml of ice-cold water and air-dried. 50 Yield: 95.7 g (92%) of the title compound Melting point: 230-231 ° C (water)

'H NMR (DMSO-d6): 8 2.4 s (3H), 3.55 s (2H).

Example 9

S5 ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetate a) 95.7 g (0.517 mol) of the compound prepared according to Example 8 are in a mixture of 550 ml of ethanol and 160 ml of concentrated sulfuric acid for 8 hours cooked. Then the reaction mixture is poured into a mixture of 500 g ice and 1500 ml Was-60 water and extracted first once with 500, then twice with 250 ml dichloromethane. The organic phase is washed twice with 400 ml of water each time and then evaporated in vacuo. First 500 ml of dichloromethane, then 250 ml of n-hexane are distilled off from the residue, and the residue obtained is purified by Va-65 vacuum distillation.

Yield: 91.3 g (73%) of the title compound Boiling point: 113-115 ° C (0.2 mmHg)

Melting point: 21 ° C

658 655

6

'H NMR (CDCI3): S 1.221 (3H), 1.30 t (3H), 2.6 s (3H), 3.85 s (2H), 4.15 q (2H), 4.25 q (2H).

b) 32 g (193 mmol) of the (5-methyl-4-cyano-3-isoxazole) acetic acid prepared according to Example 7 are refluxed in a mixture of 150 ml of ethanol and 75 ml of concentrated sulfuric acid for 16 hours. The reaction mixture is poured into a mixture of 250 ml of water and 250 g of ice and then extracted first with 150 ml, then twice with 100 ml of dichloromethane. The organic phase is washed first with 200 ml, then with 100 ml of water and then the dichloromethane is distilled off. The residue is mixed with a further 200 ml of dichloromethane and this is also distilled off.

Yield: 22 g (47%) of the title compound; the physical data correspond to those of the product obtained according to Example 9a).

Example 10

n-Butyl-l 5-methyl-4- (n-butoxycarbonylj-3-isoxazole] acetate

The procedure is as described in Example 8, but the reagent used is not ethanol, but a mixture of n-butanol and benzene, and the water formed is removed continuously. Yield: 74%

Boiling point: 130-132: C / 0.1 mmHg

H-NMR (CDCI3): 5 0.90-1.05 m (6H), 1.15-1.90 m (8H), 2.65 s (3H), 3.85 s (2H) and 4 , 15 q (4H).

Example 11

Ethyl (5-methyl-4-cyano-3-isoxa: ol) -ace did

20 g (120 mmol) of the (5-methyl-4-cyano-3-isoxazole) acetic acid prepared according to Example 7 are stirred with water cooling in 100 ml of dioxane in the presence of 18 ml (130 mmol) of triethylamine. The solution of 12.7 ml (130 mmol) of ethyl chloroformate prepared with 20 ml of anhydrous dioxane is added dropwise within 5 minutes. After stirring for 10 minutes, the precipitated triethylamine hydrochloride is filtered off. The filtrate is boiled for 30 minutes and then evaporated in vacuo. The evaporation residue is triturated with 50 ml of water and extracted with 3 x 80 ml dichloromethane. The organic phase is washed with 2 x 39 ml of water and then evaporated. First 150 ml of dichloromethane and then 75 ml of n-hexane are distilled off from the residue.

Yield: 21.5 g (92%) of the title compound Boiling point: 112-114 'C / 0.4 mmHg IR: 2300.1740 cm "1

'H NMR (CDCI3): S 1.25 t (3H), 2.60 s (3H), 3.75 s (2H), 4.25 q (2H).

Example 12

N-benzyl- (5-methyl-4-cyano-3-isoxazole) acetamide

2 g (12 mmol) of the (5-methyl-4-cyano-3-isoxazole) acetic acid prepared according to Example 7 are boiled in 20 ml of anhydrous benzene in the presence of 2.7 g (13 mmol) of phosphorus pentachloride. Then the solution is evaporated in vacuo. The residue is mixed with 20 ml of 60 ° C. warm n-heptane and the oil which separates out (2.1 g) is separated off. The oil is dissolved in 10 ml of anhydrous dioxane and 2.3 ml (20 mmol) of benzylamine are added to the solution. The mixture is left to stand for 10 minutes and then the precipitated mixture is diluted with 60 ml of water. The precipitate is filtered off, washed with water, dried and then recrystallized from 20 ml of 2-propanol.

Yield: 2.3 g (90%) of the title compound Melting point: 143 ° C IR: 3300, 2310, 1645 cm-1

'H NMR (CDC13): 8 2.50 s (3H), 3.60 s (2H), 4.35 d (2H), 6.40 m (IH), 7.15 s (5H).

Example 13

(5-methyl-4-cyano-3-isoxazole) acetanilide

10 g {60 mmol) of the (5-methyl-4-cyano-3-isoxazole) acetic acid prepared according to Example 7 are reacted in the manner described in Example 12 with 13.5 g (65 mmol) of phosphorus pentachloride. The oily crude acid chloride is dissolved in 20 ml of anhydrous dioxane and, while cooling with ice water, dropwise added within 5 minutes with the solution of 11 ml (120 mmol) of freshly distilled aniline in 30 ml of anhydrous dioxane. The reaction mixture is stirred at room temperature for 15 minutes and then diluted with 100 ml of water. The precipitated product is filtered off, washed twice with 20 ml of water, dried and then recrystallized from 80 ml of ethanol.

Yield: 8.5 g (60%) of the title compound Melting point: 175 C IR: 3250, 2300, 1660 cm-1

'H NMR (DMSO-de): 8 2.60 s (3H), 3.95 s (2H), 7.00-7.65 m (5H).

Example 14

N- [(5-methyl-4-cyano-3-isoxazole) acetyl] morpholine

10 g of the (5-methyl-4-cyano-3-isoxazole) acetic acid prepared according to Example 7 are reacted with 13.5 g (65 mmol) of phosphorus pentachloride in the manner described in Example 12. The oily crude acid chloride is dissolved in 25 ml of anhydrous dioxane and the solution is added dropwise to the solution of 10 ml (115 mmol) of morpholine prepared with 25 ml of dioxane within 2 minutes. The dioxane is distilled off in vacuo and the residue is stirred with 30 ml of water. The aqueous mixture is extracted with 3 × 30 ml of chloroform, the organic phase is separated off, washed twice with 50 ml of water each time and then evaporated in vacuo. The residue is mixed with 100 ml of dichloromethane and this is then distilled off. The product is recrystallized from 60 ml of 2-propanol.

Yield: 7.1 g (50%) of the title compound Melting point: 130-131 C IR: 2280, 1640 cm "1

'H NMR (CDCI3): 5 2.55 s (3H), 3.60 s (8H), 3.75 s (2H). Example 15

N-benzyl- (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetamide

A mixture of 50 g (207 mmol) of the ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetate prepared according to Example 9 and 23 ml (209 mmol) of benzylamine is on the oil bath (185-195 "C) Stirred for 90 minutes and then cooled. The product which separated out was triturated with 100 ml of n-hexane and then filtered. Yield: 5.4 g (91%) of the title compound Melting point: 124-125 "C. (2-propanol)

'H NMR (CDCI3): 8 1.301 (3H), 2.60 s (3H), 3.75 s (2H), 4.20 q (2H), 4.35 d (2H), 7.15 s (5H ).

Example 16

6,7-dihydro-4H-pyrano [3,4-c] isoxazole-4,6-dione

37 g (200 mmol) of the (5-methyl-4-carboxy-3-isoxazole) acetic acid prepared according to Example 8 are boiled in 100 ml of acetic anhydride for 2 minutes, then the excess of acetic anhydride is poured onto a water bath (80 ° ) distilled off. The residue is dissolved in 100 ml of anhydrous toluene and the solution is left in the refrigerator overnight. The precipitated substance is filtered off and washed with 2 x 15 ml of ice-cold toluene, then with 2 x 30 ml of n-hexane and then dried.

Yield: 22.5 g (67%) of the title compound Melting point: 170-172 "C (decomposition)

IR: 1780, 1750 cm "1

'H NMR (DMSO-d6): S 2.40 s (3H), 3.55 s (2H).

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Example 17

Diethyl (E) -2-acetyl-3-amino-2-pentene dioate

91.3 g (0.379 mol) of the compound obtained according to Example 9a) or b) are hydrogenated in 800 g of ethanol in the presence of 4 g of palladium-activated carbon under atmospheric pressure at room temperature (150-180 minutes). The catalyst is filtered off, the filtrate is evaporated in vacuo and 100 ml of n-hexane are distilled off over the residue. The residue obtained solidifies at 0 ° C. Yield: 91.2 g (98%) of the title compound Boiling point: 147-149c C / 0.4 mmHg Melting point: 41-42 ° C (ether / n-hexane)

Elemental analysis for CnHi7N05 (M = 243.26)

Calculated: C 54.31 H 7.05 N 5.76%

Found: C 54.45 H 7.10 N 5.59%

1 H NMR (CDC13): 5 1.25 t (3H), 1.30 t (3H), 2.28 s (3H), 3.55 s (2H), 4.12 q (2H), 4 , 18 q (2H).

Example 18

(Z) -3-Amino-4-cyano-5-oxo-hexenoic acid benzylamide

The solution, prepared with 200 ml of methanol, of 9 g (35.2 mmol) of the N-benzyl- (5-methyl-4-cyano-3-isoxazole) -acetamide prepared according to Example 12 is in the presence of 1 g of palladium-activated carbon at room temperature Atmospheric pressure hydrogenated until the hydrogen uptake ceases. Then the catalyst is filtered off, the filtrate is evaporated and the evaporation residue is recrystallized from 100 ml of 2-propanol.

Yield: 7.5 g (83%) of the title compound. Melting point: 163 ° C.

'H NMR (CDCI3): 8 2.15 s (3H), 3.40 s (2H), 4.30 d (2H), 7.15 s (5H), 8.55 m (IH).

Example 19

(Z) -3-amino-4'cyano-5-oxo-3-hexenoic acid anilide

7.2 g (29.8 mmol) of the (5-methyl-4-cyano-3-isoxazole) acetanilide prepared according to Example 13 are hydrogenated in 120 ml of dioxane at 60 ° C. in the manner described in Example 18.

Yield: 5.6 g (77%) of the title compound Melting point: 226: C (ethanol)

■ H NMR (DMSO-d6): 8 2.15 s (3H), 3.60 s (2H), 7.00-7.65 m (5H), 9.10 m (IH).

Example 20

N- [(Z) -3-amino-4-cyano-5-oxo-3-hexenoyl] morpholine

7 g (30 mmol) of the N - [(5-methyl-4-cyano-3-isoxazole) acetyl] morpholine prepared according to Example 14 are hydrogenated in 75 ml of methanol in the manner described in Example 18.

Yield: 4.5 g (64%) of the title compound Melting point: 171 ° C (2-propanol)

H-NMR (DMSO-d6): 8 1.95 s (3H), 3.30 s (ÎOH), 8.80 s (IH). Example 21

Ethyl [2-acetyl-3-amino-4- (N-benzylcarbamoyl) -2 (ej-butenoate]

50 g (165 mmol) of the N-benzyl- (5-methyl-4-ethoxycarbonyl-3-isoxazole) -acetamide prepared according to Example 15 are added to the

658 655

hydrogenated in the manner described in Example 18 and the product isolated in the manner given there.

Yield: 50 g (99%) of the title compound Melting point: 126-127 ° C (2-propanol / n-hexane) = 1: 2) IR: 3250-3050, 1690, 1650 cm "'

H-NMR (CDCI3): 8 1.20 t (3H), 2.20 s (3H), 3.30 s (2H), 4.15 q (2H), 4.30 d (2H), 7 , 10 s (5H), 7.65 m (9H).

Example 22

À thyl- [3-amino-4-cyano-5-oxo-3 (Z) hexanoate]

11 g (56.6 mmol) of the ethyl (5-methyl-4-cyano-3-isoxazole) acetate prepared according to Example 11 are hydrogenated and worked up in the manner described in Example 18.

Yield: 11 g (99%) of the title compound Melting point: 70-71 ° C (diethyl ether)

IR: 3280.3100, 2260, 1730 cm "1

H-NMR (CDC13): 8 1.25 t (3H), 2.30 s (3H), 3.55 s (3H), 4.15 q (2H), 7.95 m (IH), 11 , 0 m (IH).

Example 23

(2RS, 3RS, 4SR) -4- (benzylamino) -2-methyl-6-oxo-tetrahydropyran-3-carboxylic acid hydrochloride

To the solution of 16 g (53 mmol) of the compound prepared according to Example 21 prepared with 150 ml of glacial acetic acid, 9 g (approximately 120 mmol) of approximately 90% sodium cyanotrihydroborate are added in small portions at room temperature with stirring within 30 minutes. The reaction mixture is stirred for a further 3 hours at room temperature and finally for 10 minutes on a water bath (80e C). The reaction mixture, cooled to room temperature, is mixed with 6.5 ml (60 mmol) of benzaldehyde and left to stand at room temperature for 12 hours. Then another 5.5 g (about 75 mmol) of about 90% sodium cyanotrihydroborate are added in small portions with stirring within 30 minutes. The reaction mixture is stirred at room temperature for 3 hours, then evaporated in vacuo and 300 ml of n-heptane are added to the residue. This is distilled off. Then 300 ml of ethyl acetate and then dropwise and carefully 300 ml of 10% aqueous ICalium hydrogen carbonate solution are added to the residue. After adding 30 g of solid potassium hydrogen carbonate, the organic phase is separated off. The aqueous phase is extracted twice with 200 ml of ethyl acetate. The combined organic phases are washed first with 200 ml, then with 100 ml of 10% aqueous potassium hydrogen carbonate solution and then evaporated in vacuo. The residue is boiled with 150 ml of concentrated aqueous hydrochloric acid for 3 hours. The mixture is evaporated in vacuo and the solid residue is triturated with 100 ml of acetone and left to stand for 5 minutes. The product is filtered off, washed twice with in each case 25 ml of acetone, then triturated twice with in each case 30 ml of water, filtered off and dried in air at 80.degree.

Yield: 6.7 g (42%) of the title compound Melting point: 163-164 ° C (decomposition)

H-NMR (DMSO-d6 + CDC13): 8 1.31 d (3H), J = 5.6 Hz; 3.08 dd + 3.28 dd (2H, J = 15.5 Hz and 8.0 Hz or 15.5 Hz and 9 Hz); 3.38 dd (1H, J = 3 Hz and 3.5 Hz); 4.04 dt (1H, J = 3 Hz and 8 Hz); 4.21 s (2H); 5.24 dq (1H, J = 3.5 Hz and 6 Hz); 7.32-7.73 m (5H).

7

5

10th

15

20th

25th

30th

35

40

45

50

55

R

Claims (14)

658 655 2nd PATENT CLAIMS 1. Compounds of general formula I X Y-CH , ü 1 H 1 l | "O-A-o '" "3C' ^ O'n (IIa) (I). in which X and Y independently of one another represent a nitrile group, optionally activated carboxyl group or groups of the formulas —COOZ or - CONRR ', in which Z represents an alkyl group having 1 to 6 carbon atoms and R and R' represent hydrogen, are a phenyl or benzyl group or form a heterocycle with the nitrogen atom, or X and Y together are an anhydride group of the formula Form 0 = C-0-C = 0. I I 2. (5-methyl-4-cyano-3-isoxazole) acetic acid as a compound according to claim 1. 3. (5-methyl-4-carboxy-3-isoxazole) acetic acid as a compound according to claim 1. 4. ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetate as a compound according to claim 1. 5. n-Butyl- [5-methyl-4- (n-butoxycarbonyl) -3-isoxazole] acetate as a compound according to claim 1. 6. N-benzyl- (5-methyl-4-cyano-3-isoxazole) acetamide as a compound according to claim 1. 7. (5-methyl-4-cyano-3-isoxazole) acetanilide as a compound according to claim 1. 8. ethyl (5-methyl-4-cyano-3-isoxazole) acetate as a compound according to claim 1. 35 9. N - [(5-methyl-4-cyano-3-isoxazole) acetyl] morpholine as a compound according to claim I. 10. N-benzyl- (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetamide as a compound according to claim 1. 11. 6,7-dihydro-4H-pyrano [3.4-c] isoxazole-4,6-dione as a compound according to claim 1. 12. A process for the preparation of isoxazole derivatives of the general formula I according to claim 1, wherein Y is a carboxyl group and X is a nitrile group, characterized in that the compound of the formula II and / or IIa 45 (II) reacted with a strong base and reacting the product obtained in the presence of a catalyst with an alkanol having 1 to 6 carbon atoms and isolating the compound obtained, io 14. The method according to claim 13, characterized in that a mineral acid is used as the catalyst. 15. A process for the preparation of isoxazole derivatives of the general formula I according to claim 1, in which Y is a group - CONRR 'and X is a group --COOZ, characterized in that ge-15 that the compound of formula II and / or IIa and or X J JLoJ o cr h3c (Ii) (IIa) is reacted with a strong base and the product obtained is reacted in the presence of a catalyst with an alkanol having 1 to 6 carbon atoms and the compound obtained is used to give a group - NRR 'in which the meaning of R and R' is the same as above , suitable amine and the resulting compound of formula I isolated. 16. The method according to claim 15, characterized in that aniline, benzylamine or morpholine is used as the amine.